Acute pancreatitis has an incidence of up to 5/10,000 and can cause death in 30% of those with severe disease. Since pancreatitis is often caused by alcohol abuse and increases in incidence with age, the disease is frequently encountered in our Veteran population. Treatments for pancreatitis have changed little over the past 25 years; one of the mainstays of therapy is intravenous fluid. Optimization of such therapy may affect the course of disease and risk and/or severity of disease in susceptible individuals (ERCP/papillotomy/surgery/trauma). During our current funding period, we reported the effects of an acid load in pancreatitis (Gastroenterology 137: 1083-1092, 2009) . We found that an acute acid load is a potent sensitizer both in vivo and in vitro using rodent models of pancreatitis. While pursuing our studies, we found unexpected effects of standard intravenous fluids on pancreatitis. The two most commonly used intravenous fluids used in pancreatitis are normal saline (NL) and lactated Ringer's (LR). The composition of both of these fluids might have negative effects in this disease. Thus, NS is usually acidic (pH often <5.5) and when given in large amounts can present a large acid load. LR is usually less acidic (pH ~6.5), but contains high concentrations of calcium, magnesium, and lactate. Using in vivo and cellular models of acute pancreatitis, we have made the following preliminary observations. Short-term in vivo studies show that LR may have time-dependent effects on pancreatitis responses that differ from NS. Studies in isolated groups of acinar cells (acini) suggest lactate affects pancreatitis responses independent of extracellular pH. These responses are observed within the concentration range of lactate seen in physiologic and pathologic conditions (1-20 mM). These lactate responses may be mediated by GPR81, the only G-protein coupled receptor activated by lactate. Using PCR and immunoblot analysis, GPR81 was localized to the pancreatic acinar cell. GPR81 expression was maintained during experimental pancreatitis. Lactate may act through GPR81 to affect pancreatitis responses. The concentration of sodium also differs among intravenous solutions; administering fluids low in sodium can reduce its levels in the blood (hyponatremia). We find that pancreatitis responses can be modulated by the concentration of extracellular sodium; sodium-hydrogen exchangers may mediate this response. This affect of hyponatremia may be through an indirect of affect on cytosolic pH of the acinar cell. We propose to extend our preliminary data by pursuing the following specific objectives: 1) Examine the effects of standard intravenous buffers in in vivo models of mild and severe pancreatitis, 2) Investigate the effects of lactate and its receptor, GPR81, on physiologic and pancreatitis responses including cell signaling in acini and in vivo, 3) Study the effects extracellular sodium and sodium- hydrogen exchange on pancreatitis responses and acinar cell pH. The findings of these studies could lead to modifications in intravenous solutions that optimize their effectiveness for the prevention and treatment of acute pancreatitis and provide insights into disease mechanisms. ) PUBLIC HEALTH RELEVANCE: Acute pancreatitis is an inflammatory disease that begins in the pancreas and can involve multiple organs when severe. About 25% of patients with will have severe disease, and 30% of those will die. The most common causes of acute pancreatitis are alcohol abuse and gallstones. Because both conditions are common in our population, the incidence of acute pancreatitis is high in Veterans. Although the most important therapy for this disease is intravenous fluids, there are many types of fluids available and these differ in some of their basic components. Using animal and cellular model of pancreatitis, we have discovered that some standard fluids can affect pancreatitis responses. The goal of our work is to use this information to design the optimal intravenous fluid treating acute pancreatitis.